Lipophilicity

The OECD guideline for studies on percutaneous penetration to be used in hazard and risk evaluations prescribes experimental conditions with optimal barrier integrity of the skin, which in many occupational settings probably is not true. Thus, workers may have compromised skin due to chemical or mechanical damage, due to different medical conditions (eczema, dermatitis, skin irritation) or related to occupational scenarios involving prolonged wet work. The present study used the OECD guideline procedures to study the in vitro percutaneous penetration through human skin of a number of model substances (glyphosat, caffeine, benzoic acid, malathion) covering a range of solubilities. Further, we studied the extent to which a slightly damaged skin would change the rate, the amount absorbed during dermal exposure and the distribution of chemical deposition between epidermis and dermis. The present study demonstrates that a limited damage to the skin significantly increases the permeability coefficient (K p) as well as total percutaneous penetration of chemicals, and most significantly for those compounds that due to their physicochemical characteristics (the most hydrophilic as well as the most lipophilic) have low penetration rates through intact skin. The present experiment not only confirms the proportionality between lipophilicity and potential for percutaneous penetration, but also illustrates that at a certain degree of lipophilicity of a model compound, the different skin compartments become more attractive for temporary deposition of model compounds. Moreover, a clear change from epidermal deposition towards a dominating dermis deposition of chemicals temporarily deposited within the skin is seen following damage to the skin barrier. Thus, the distribution of chemicals within the skin compartments is affected by the physicochemical characteristics of the chemicals as well as by the integrity of the skin. This observation may have implications when evaluating the possibility of removing chemicals from the skin through different cleansing procedures following unintended dermal exposures.

Traditional lipophilicity parameters (log P and log D) are well-known physico-chemical descriptors largely used in QSAR studies. Besides their numerical value, log P data contain a variety of information about inter- and intramolecular forces affecting partitioning and its related biological phenomena. The deconvolution of information from log P can be accessed only by adequate interpretative tools, such as new lipophilic-combined descriptors, of which features and some applications are presented in this review.

Introduction: The lymphatic system has a critical role in the immune system’s
recognition and response to disease and it is an additional circulatory system
throughout the entire body. Extensive multidisciplinary investigations have
been carried out in the area of lymphatic delivery, and lymphatic targeting
has attracted a lot of attention for providing preferential chemotherapy
and improving bioavailability of drugs that undergo hepatic first-pass
metabolism.
Areas covered: This review focuses on progress in the field of lymphatic
therapeutics and diagnosis. Moreover, the anatomy and physiology of the
lymphatic system, particulate drug carriers and different physicochemical
parameters of both modified and unmodified particulate drug carriers and
their effect on lymphatic targeting are addressed.
Expert opinion: Particulate drug carriers have encouraged lymphatic targeting,
but there are still challenges in targeting drugs and bioactives to specific
sites, maintaining desired action and crossing all the physiological barriers.
Lymphatic therapy using drug-encapsulated lipid carriers, especially liposomes
and solid lipid nanoparticles, emerges as a new technology to provide
better penetration into the lymphatics where residual disease exists. Size is
the most important criteria when designing nanocarriers for targeting lymphatic
vessels as the transportation of these particles into lymphatic vessels
is size dependent. By increasing our understanding of lymphatic transport
and uptake, and the role of lymphatics in various diseases, we can design
new therapeutics for effective disease control.

The nitrogen-containing bisphosphonates (N-BPs) are a major class of drugs for the treatment of diseases characterized by excessive bone resorption. Farnesyl pyrophosphosphate synthase (FPPS), one of the key enzymes involved in the mevalonate pathway, is the major molecular target of N-BPs. From the comparative docking study of our compounds with many structurally related lead compounds such as zoledronate and pamidronate we could observe how our compounds might bind to the FPPS binding site, based on the knowledge of the structure of similar active sites. We redocked zoledronate and pamidronate into the active site of the enzyme, and then we replaced with our compounds in order to compare the binding mode of both ligand and the test compound.

The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I(1)-R). Selective I(1)-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I(1) receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I(1)-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d,p) and Becke3LYP/6-31G(d,p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statis...

In this Letter, we provide the structure–activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t1/2 = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t1/2 = 34 h.We describe our strategy to discover a selective inhibitor of COX-2 with a shorter human half-life compared with the previous clinical candidate SD-8381 (5c-(S), t1/2 ∼160 h). In this paper, we disclose a series of selective COX-2 inhibitors based on the benzopyran template that display potency against COX-2 in animal models of pain and inflammation. We also discussed the discovery of two COX-2 binding modes and utilizing the microsomal data as a filter leading to the discovery of clinical candidate 29b-(S) (SC-75416), successfully advanced through a phase II efficacy trial.